Cocaine is a significant risk factor for contracting HIV-1 infection and subsequently developing AIDS. The proposed research is aimed to dissect the role of cocaine and HIV-associated epigenetic mechanisms in the development of HIV-associated neurocognitive disorders (HAND). In recent years, chromatin remodeling has emerged as an important regulatory mechanism for drug addiction and also in development of neurodegenerative disorders. In the current study, we will focus on HDAC2 since it is known to play a critical role in cognitive function by regulating the density of dendritic spines and influencing synaptic transmission in mature neurons. However, the role of HDAC2 in development of HAND is not elucidated yet in the context of cocaine. In our published and preliminary studies, we found that HIV-1 Tat protein and HIV-1 infection upregulate HDAC2 expression with concomitant downregulation of CREB and CamKIIa and 17 other genes that are known to regulate synaptic plasticity. Further we have shown for the first time that cocaine significantly upregulated HDAC2 gene expression and downregulated miR-155 and transfection with miR-155 significantly inhibited HIV infection. Accordingly, we hypothesize that cocaine acts a co-factor in neuropathogenesis of HIV infection by modulating HDAC2 expression in CNS cells leading to transcriptional repression of genes that regulate neuronal activity and synaptic plasticity. The specific goals are to determine: 1) whether cocaine in association with HIV-1 virus modulates HDAC2 which in turn negatively regulates synaptic plasticity/ memory genes in primary human microglia, hippocampal neurons and astrocytes thereby contributing to the progression of HAND; 2) whether inhibition of HDAC2 reverses the effects of cocaine and HIV-1 virus on neuronal plasticity genes and dendritic spine density and 3) can delivery of HDAC2 specific siRNA and miR-155 across the in vitro blood-brain barrier (BBB) model and in HIV-E SCID cocaine mouse model using transferrin coupled liposomal nanoformulation be explored as a therapeutic strategy for HAND. Thus, an understanding of cocaine and HIV-associated epigenetic changes and its implications in neuropathogenesis will have translational significance for therapeutic targeting and control of HAND in HIV-infected cocaine users.